Worldwide, heterosexual transmission accounts for most HIV-1 infections. Clearly, controlling heterosexual transmission of HIV-1 would be a significant step toward eliminating this global epidemic. To achieve this goal, it will be important to delineate the cellular and molecular events that affect virus transmission. Although both inflammatory and ulcerative sexually transmitted infections (STIs) enhance sexual transmission of HIV-1, the underlying mechanisms leading to this enhancement have not been fully elucidated. Enhanced susceptibility to infection may be due to a number of factors, including the disruption of the integrity of the cervicovaginal epithelial barrier, recruitment of HIV-1 target cells such as Langerhans/dendritic cells (LC/DC), macrophages (M?) and T lymphocytes to sites of inflammation, and direct activation of target cells by STIs. A common feature of STI pathogens is that they encode ligands for members of the Toll-like receptor (TLR) family of pattern recognition receptors and these ligand-activated TLRs can both activate HIV-1 target cells and induce local inflammatory responses. Ligand-activated nuclear receptors (NR), including peroxisome proliferator activated receptor (PPAR), liver X receptor (LXR), glucocorticoid receptor (GR), are potent inhibitors of TLR-induced inflammatory gene expression in M?, LC/DC, and epithelial cells. In addition, retinoic acid receptor (RAR) and PPAR ligands have been shown to repress HIV-1 gene expression. Our initial goal is to determine the role of Neisseria gonorrhoeae exposure or TLR-signaling in augmenting HIV-1 infection of target cells that are found in the cervicovaginal mucosae. Our major and long-term goal is to examine the potential role of ligand-activated NR as inhibitors of HIV-1 transmission. We will test the hypothesis that ligand-activated NR act by: 1) directly repressing HIV-1 transcription, and 2) by limiting the STI or TLR-induced inflammatory microenvironment that favors HIV-1 replication. To achieve these goals, we will 1) evaluate the impact of NR/TLR crosstalk on HIV-1 replication and inflammatory gene expression in primary LC, DC, MF and T cells, 2) determine the mechanism(s) of TLR-modulated HIV-1 transcription and how it is regulated by NR signaling, and 3) examine the effects of NR/TLR crosstalk on HIV-1 infection of target cells and inflammation in vaginal and cervical tissue explants and in an organotypic model of the human vagina. PUBLIC HEALTH RELEVANCE: World-wide, most new infections with HIV-1, the virus that causes AIDS, occur in women who have had intercourse with infected men. The ability of HIV-1 to be transmitted to women is greater in those women who are also infected with other sexually transmitted diseases. This is partly due to the fact that these other diseases cause inflammation. We are studying a novel class of drugs that we believe inhibit HIV-1 infection by blocking both inflammation and the ability of HIV-1 to grow. We will test these drugs for their ability to inhibit HIV-1 transmission using purified cells and a unique laboratory-derived tissue model of the female reproductive tract.